Current Diabetes Reports

, Volume 9, Issue 6, pp 447–452

What is the role of renin inhibition in the treatment of diabetic kidney disease?

Article

Abstract

Inhibition of the renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in preventing and treating diabetic nephropathy. However, despite documented beneficial effects of RAAS inhibitors in diabetic patients with nephropathy, reversal of the progressive course of this disorder or at least long-term stabilization of renal function are often difficult to achieve, and many patients still progress to end-stage renal disease. Incomplete inhibition of the RAAS has been postulated as one of the reasons for unsatisfactory therapeutic responses to RAAS inhibition in some patients. Inhibition of renin, a rate-limiting step in the RAAS activation cascade, is the logical approach to overcome at least some of the above-mentioned problems associated with the treatment with traditional RAAS inhibitors. This article focuses on experimental and clinical studies evaluating the two principal approaches to renin inhibition: direct renin inhibition with competitive inhibitors (eg, aliskiren) and inhibition of the (pro)renin receptor.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Weir MR: Renin inhibitors: novel agents for renoprotection or a better angiotensin receptor blocker for blood pressure lowering? Curr Opin Nephrol Hypertens 2007, 16:416–421.CrossRefPubMedGoogle Scholar
  2. 2.
    Leibovitz E, Schiffrin EL: Novel drugs targeting hypertension: renin inhibitors and beyond. J Cardiovasc Pharmacol 2007, 50:3–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Muller DN, Luft FC: Direct renin inhibition with aliskiren in hypertension and target organ damage. Clin J Am Soc Nephrol 2006, 1:221–228.CrossRefPubMedGoogle Scholar
  4. 4.
    Urata H, Strobel F, Ganten D: Widespread distribution of human chymase. J Hypertens 1994, 12:S17–S22.Google Scholar
  5. 5.
    Nguyen G, Delarue F, Burckle C, et al.: Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002, 109:1417–1427.PubMedGoogle Scholar
  6. 6.
    Huang Y, Wongamorntham S, Kasting J, et al.: Renin increases mesangial cell transforming growth factorbeta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int 2006, 69:105–113.CrossRefPubMedGoogle Scholar
  7. 7.
    Ichihara A, Suzuki F, Nakagawa T, et al.: Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. J Am Soc Nephrol 2006, 17:1950–1961.CrossRefPubMedGoogle Scholar
  8. 8.
    Schefe JH, Menk M, Reinemund J, et al.: A novel signal transduction cascade involving direct physical interaction of the renin/prorenin receptor with the transcription factor promyelocytic zinc finger protein. Circ Res 2006, 99:1355–1366.CrossRefPubMedGoogle Scholar
  9. 9.
    Luft FC, Weinberger MH: Antihypertensive therapy with aliskiren. Kidney Int 2008, 73:679–683.CrossRefPubMedGoogle Scholar
  10. 10.
    Feldt S, Maschke U, Dechend R, et al.: The putative (pro)renin receptor blocker HRP fails to prevent (pro)renin signaling. J Am Soc Nephrol 2008, 19:743–748.CrossRefPubMedGoogle Scholar
  11. 11.
    Feldman DL, Jin L, Xuan H, et al.: Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension 2008, 52:130–136.CrossRefPubMedGoogle Scholar
  12. 12.
    Ganten D, Wagner J, Zeh K, et al.: Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes. Proc Natl Acad Sci U S A 1992, 89:7806–7810.CrossRefPubMedGoogle Scholar
  13. 13.
    Durvasula RV, Shankland SJ: Activation of a local renin angiotensin system in podocytes by glucose. Am J Physiol Renal Physiol 2008, 294:F830–F839.CrossRefPubMedGoogle Scholar
  14. 14.
    Kelly DJ, Zhang Y, Moe G, et al.: Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats. Diabetologia 2007, 50:2398–2404.CrossRefPubMedGoogle Scholar
  15. 15.
    Persson F, Rossing P, Schjoedt KJ, et al.: Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes. Kidney Int 2008, 73:1419–1425.CrossRefPubMedGoogle Scholar
  16. 16.
    Persson F, Rossing P, Reinhard H, et al.: Renal effects of aliskiren compared to and in combination with irbesartan in patients with type 2 diabetes, hypertension and albuminuria. Diabetes Care 2009 Jul 8 (Epub ahead of print).Google Scholar
  17. 17.
    Parving HH, Persson F, Lewis JB, et al.: Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008, 358:2433–2446.CrossRefPubMedGoogle Scholar
  18. 18.
    Rossing K, Parving HH: Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy. Diabetes Care 2005, 28:2106–2112.CrossRefPubMedGoogle Scholar
  19. 19.
    Luetscher JA, Kraemer FB, Wilson DM, et al.: Increased plasma inactive renin in diabetes mellitus: a marker of microvascular complications. N Engl J Med 1985, 312:1412–1417.PubMedCrossRefGoogle Scholar
  20. 20.
    Deinum J, Ronn B, Mathiesen E, et al.: Increase in serum prorenin precedes onset of microalbuminuria in patients with insulin-dependent diabetes mellitus. Diabetologia 1999, 42:1006–1010.CrossRefPubMedGoogle Scholar
  21. 21.
    Suzuki F, Hayakawa M, Nakagawa T, et al.: Human prorenin has “gate and handle” regions for its non-proteolytic activation. J Biol Chem 2003, 278:22217–22222.CrossRefPubMedGoogle Scholar
  22. 22.
    Ichihara A, Hayashi M, Kaneshiro Y, et al.: Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin. J Clin Invest 2004, 114:1128–1135.PubMedGoogle Scholar
  23. 23.
    Takahashi H, Ichihara A, Kaneshiro Y, et al.: Regression of nephropathy developed in diabetes by (Pro)renin receptor blockade. J Am Soc Nephrol 2007, 18:2054–2061.CrossRefPubMedGoogle Scholar
  24. 24.
    Batenburg WW, Krop M, Garrelds IM, et al.: Prorenin is the endogenous agonist of the (pro)renin receptor. Binding kinetics of renin and prorenin in rat vascular smooth muscle cells overexpressing the human (pro)renin receptor. J Hypertens 2007, 25:2441–2453.CrossRefPubMedGoogle Scholar
  25. 25.
    Feldt S, Batenburg WW, Mazak I, et al.: Prorenin and renin-induced extracellular signal-regulated kinase 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide. Hypertension 2008, 51:682–688.CrossRefPubMedGoogle Scholar
  26. 26.
    Muller DN, Klanke B, Feldt S, et al.: (Pro)renin receptor peptide inhibitor “handle-region” peptide does not affect hypertensive nephrosclerosis in Goldblatt rats. Hypertension 2008, 51:676–681.CrossRefPubMedGoogle Scholar
  27. 27.
    Veniant M, Menard J, Bruneval P, et al.: Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver. J Clin Invest 1996, 98:1966–1970.CrossRefPubMedGoogle Scholar
  28. 28.
    Burckle C, Bader M: Prorenin and its ancient receptor. Hypertension 2006, 48:549–551.CrossRefPubMedGoogle Scholar
  29. 29.
    Kaneshiro Y, Ichihara A, Sakoda M, et al.: Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats. J Am Soc Nephrol 2007, 18:1789–1795.CrossRefPubMedGoogle Scholar
  30. 30.
    Ichihara A, Kaneshiro Y, Takemitsu T, et al.: Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension 2006, 47:894–900.CrossRefPubMedGoogle Scholar
  31. 31.
    Peters B, Grisk O, Becher B, et al.: Dose-dependent titration of prorenin and blood pressure in Cyp1a1ren-2 transgenic rats: absence of prorenin-induced glomerulosclerosis. J Hypertens 2008, 26:102–109.CrossRefPubMedGoogle Scholar
  32. 32.
    Mercure C, Prescott G, Lacombe MJ, et al.: Chronic increases in circulating prorenin are not associated with renal or cardiac pathologies. Hypertension 2009, 53:1062–1069.CrossRefPubMedGoogle Scholar
  33. 33.
    Nguyen G, Danser AH: Prorenin and (pro)renin receptor: a review of available data from in vitro studies and experimental models in rodents. Exp Physiol 2008, 93:557–563.CrossRefPubMedGoogle Scholar
  34. 34.
    Satofuka S, Ichihara A, Nagai N, et al.: (Pro)renin receptor-mediated signal transduction and tissue renin-angiotensin system contribute to diabetes-induced retinal inflammation. Diabetes 2009, 58:1625–1633.CrossRefPubMedGoogle Scholar
  35. 35.
    Parving HH, Brenner BM, McMurray JJ, et al.: Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant 2009, 24:1663–1671.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Division of Nephrology and HypertensionOregon Health & Science UniversityPortlandUSA

Personalised recommendations